Gilson, Clare; (2019) Improving Outcomes in Prostate Cancer. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

The results of the STAMPEDE trial demonstrate that intensified systemic therapy with docetaxel or abiraterone added to androgen deprivation therapy (ADT) improves overall survival (OS). Treatment benefit and tolerance vary, therefore prognostic and predictive biomarkers able to inform treatment selection are required to improve patient outcomes. Through performing a systematic review and meta-analysis I contextualised the celecoxib and zoledronic acid (celecoxib-ZA) results with the aim of understanding the intriguing synergistic therapeutic effect that was only seen in metastatic disease. Secondly, I explored whether prostate-specific antigen (PSA) response, assessed after commencing ADT, and PSA nadir assessed after completion of docetaxel, are prognostic of OS. Through collaboration with industry partners, I assessed the feasibility of performing targeted nextgeneration sequencing (tNGS) using formalin-fixed paraffin embedded (FFPE) prostate tumour samples. I explored the genomic profile of mCSPC and sought prevalence data to inform the evaluation of therapies such as poly ADP ribose polymerase inhibitors (PARPi) in homologous recombination deficient (HRD) cancers. No other trials evaluating a cox-2 inhibitor with a bisphosphonate were identified. However, supported by pre-clinical data, an immunological mechanism mediated by γδ T cells is proposed to explain the observed synergy. This strengthens the need for future trials and informs parallel translational research. PSA response can be used to risk-stratify patients shortly after commencing ADT and may be useful in informing the use of docetaxel. PSA nadir, assessed after completion of docetaxel, was also prognostic of OS and may be used to identify patients who remain at high risk where additional systemic therapies e.g. abiraterone, should be evaluated. The genomic study revealed that 94% (108/115) of sequenced samples had ≥1 pathogenic mutation although individual mutation frequencies remain low and pathway aberrations often co-exist, which would necessitate hierarchical allocation if used to guide treatment. The prevalence of HRD is clinically significant (15%) however the screening burden is considerable, compounded by variable sample quality, compromising the sequencing success rate (64%). These data support the further evaluation of the combination of cox-2 inhibitors and bisphosphonates and the use of PSA-based outcomes in risk-stratification, whilst the genomic feasibility and prevalence data will inform future trial designs incorporating molecular stratification.

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